PEGylated carboxyhemoglobin bovine (SANGUINATE) is a dual action carbon monoxide releasing (CO)/oxygen (O2 ) transfer agent for the treatment of hypoxia. Its components inhibit vasoconstriction, decrease extravasation, limit reactive oxygen species production, enhance blood rheology, and deliver oxygen to the tissues. Animal models of cerebral ischemia, peripheral ischemia, and myocardial ischemia demonstrated SANGUINATE's efficacy in reducing myocardial infarct size, limiting necrosis from cerebral ischemia, and promoting more rapid recovery from hind limb ischemia. In a Phase I trial, three cohorts of eight healthy volunteers received single ascending doses of 80, 120, or 160 mg/kg of SANGUINATE. Two volunteers within each cohort served as a saline control. There were no serious adverse events. Serum haptoglobin decreased, but did not appear to be dose related. The T1/2 was dose dependent and ranged from 7.9 to 13.8 h. In addition to the Phase I trial, SANGUINATE was used under an expanded access emergency Investigational New Drug. SANGUINATE was found to be safe and well tolerated in a Phase I clinical trial, and therefore it will advance into further clinical trials in patients.
2019) Microvascular and systemic responses to novel PEGylated carboxyhaemoglobin-based oxygen carrier in a rat model of vaso-occlusive crisis, Artificial Cells, Nanomedicine, and Biotechnology, 47:1, 95-103, ABSTRACT Hypoxia drives sickle cell disease (SCD) by inducing sickle cell haemoglobin to polymerize and deform red blood cells (RBC) into the sickle shape. A novel carboxyhaemoglobin-based oxygen carrier (PEG-COHb; PP-007) promotes unsickling in vitro by relieving RBC hypoxia. An in vivo rat model of vaso-occlusive crisis (VOC) capable of accommodating a suite of physiological and microcirculatory measurements was used to compare treatment with PEG-COHb to a non-oxygen carrying control solution (lactated ringer's [LRS]). Male Sprague-Dawley rats were anesthetized and surgically prepared to monitor microvascular interstitial oxygenation (P ISF O 2 ), cardiovascular parameters and blood chemistry. Human homozygous SCD RBCs were isolated and exchange transfused into the rats until the distal microcirculation of the exteriorized spinotrapezius muscle was hypoxic and RBC aggregates were visualized. VOC was left untreated (Sham) or treated 15 min later with PEG-COHb or LRS and observed for up to 4 h. Treatment with PEG-COHb showed better improvement of P ISF O 2 , end-point lactate, mean arterial pressure and survival duration compared to Sham and LRS. Restoring P ISF O 2 was associated with relieving the RBC aggregates driving VOC, which then affected other study metrics. Compared to LRS, PEG-COHb's oxygen-carrying properties were key to improved outcomes. ARTICLE HISTORY
Background: Pain during Vaso-Occlusive Crisis (VOC) is a hallmark of sickle cell disease (SCD) as deoxygenated (sickled) red blood cells (RBC) aggregate in the microvasculature due to Hemoglobin S (HbS) polymerization. PEGylated carboxyhemoglobin bovine (PEG-COHb; SANGUINATE®) was designed as a gas transfer agent to depolymerize HbS resulting from hypoxia. Prior in vitro studies have shown PEG-COHb capability to transfer carbon monoxide (CO) and oxygen (O2) to SCD hypoxic RBCs, reversing sickling. A prospective, randomized, single-dose Phase II clinical study is in progress (NCT02411708) evaluating the safety and efficacy of PEG-COHb in the treatment of severe VOC including pain reduction in the ambulatory setting. This study is also evaluating the levels of RBC sickling following treatment and association with pain scoring. Methods: Participants were randomized to a PEG-COHb (320 mg/kg) or saline (placebo) arm, in addition to standard treatment and IV opioid per institutional practice. Pain was assessed using a 10-point pain scale at screening, pre-infusion, hourly until discharge, 24-hours, 72-hours, and Day 7 post-infusion. Blood was collected at pre-infusion, time for readiness to discharge and 72 hours post-infusion to assess RBC shape morphology changes using image-based flow cytometry. Results: Interim results showed PEG-COHb treated subjects experienced significant reduction at discharge in pain score of 4.3 (±0.3) compared to 2.4 (±0.6) reduction in the placebo arm (p<0.01) (Fig 1). All PEG-COHb participants exhibited RBC morphology changes consistent with unsickling shortly after administration (Fig 2). There were no drug-related severe adverse events. Conclusions: PEG-COHb appeared to be safe, well tolerated, and associated with significantly reduced pain scores. The flow cytometry analysis of blood samples revealed PEG-COHb treatment reverted RBC to a more normal round morphology when compared to the placebo group. Individual patient data showed a trend between RBC unsickling (roundness) and pain score reductions. These results are consistent with depolymerization of HbS resulting from transfer of CO and/or O2 to sickled RBCs and O2 delivery to hypoxic tissue. This study supports advanced clinical trials of PEG-COHb as a potential therapy to reduce the pain associated with VOC. Disclosures Buontempo: Prolong Pharmaceuticals: Employment. Jubin: Prolong Pharmaceuticals: Employment. Buontempo: Prolong Pharmaceuticals: Employment. Real: Prolong Pharmaceuticals: Employment. Kazo: Prolong Pharmaceuticals: Employment. O'Brien: Prolong Pharmaceuticals: Employment. Adeel: Prolong Pharmaceuticals: Employment. Abuchowski: Prolong Pharmaceuticals: Employment, Membership on an entity's Board of Directors or advisory committees.
Background: Red blood cell (RBC) sickling is the hallmark phenotype of Sickle Cell Disease (SCD) resulting from an inherited hemoglobin (HbS) point mutation genotype. Sickling is a direct consequence of HbS polymerization that occurs as RBC encounter low oxygen environments. Sickled RBCs have increased rigidity restricting their passage through the microvasculature that can lead to a vaso-occlusive crisis (VOC). VOCs are painful, debilitating and can be associated with more severe co morbidities including acute chest syndrome, leg ulcers and stroke. Treatments for VOC are limited and include IV hydration and opioid for pain control. Extensive VOC events often require hospitalization, supplemental oxygen and transfusions. Improved therapies that can be administered early during VOC that directly target the causative RBC sickling events are warranted. PEGylated carboxyhemoglobin bovine (Sanguinate SG) is currently in clinical development being evaluated for the ability to treat the comorbidities of SCD including VOC. SG carries oxygen (O2) and/or carbon monoxide (CO) in the mammalian vasculature for delivery to tissues to synergistically treat inflammation and vasoconstriction and other comorbidities characterized by tissue hypoxia. Early intervention of VOC with SG treatment could limit the crisis event and reduce pain severity while providing a timely crisis resolution thereby reducing the likelihood of more severe VOC clinically related complications. Methods: SG treatment effects were evaluated under controlled environmental conditions to determine its capacity for gas exchange with RBCs obtained with IRB consent from healthy and SCD volunteers. Carboxyhemoglobin and oxyhemoglobin levels were monitored to determine dose and time effects as well as the repetitive capacity of SG to facilitate gas transfer processes. RBC treated samples were also analyzed by light microscopy and image capture flow cytometry to visualize and quantify the effects of SG treatment on reversing sickled SCD RBC. A PEGylated bovine serum albumin (PBSA) product was also produced and analyzed in parallel as a control agent. Results: SG addition to normal oxygenated RBC resulted in CO and O2 exchange between RBC and SG that followed mass balance and reached equilibrium in closed system. Kinetic analysis revealed SG rapidly transferred its CO component to oxygenated RBC with concomitant O2 loading of SG. Using experimentally loaded RBC with CO and SG with O2 produced similar reciprocal gas exchange results. Additionally the primary RBC/ SG reaction products were isolated and cycled demonstrating the ability of SG to continually facilitate gas transfer through multiple exposure events. Similar studies using SG, oxygenated SG (produced by an RBC exchange reaction) or PBSA control were conducted with SCD RBC. Sickling was induced by incubation of RBC in a hypoxic chamber for 3 hours prior to SG or control treatments. After 2 hours of treatment, cells were fixed by addition of glutaraldehyde. Photomicroscopy showed a marked reduction in the sickled RBC population with both SG or oxygenated SG treatments but not with the PBSA control (Fig. 1). Results from imaging flow cytometry further supported the microscopy findings and revealed a significant quantitative reduction in the percentage of sickled RBC levels. Summary: RBC rheology and lifespan are negatively impacted by repetitive HbS polymerization/de-polymerization cycling and treatments that reverse RBC sickling during a VOC event could be expected to provide broad clinical benefits through reduction of SCD comorbidities. SG was designed to promote CO and oxygen transfer in concentration dependent manners providing physiological supplementation of O2 transport/delivery in conditions of hemolytic or ischemic anemia. These ex vivo data demonstrated for the first time that under controlled conditions, a therapeutic agent could be observed serving as an active gas transport agent providing either CO or O2 to sickled RBCs, prompting rapid unsickling. Furthermore, the use of image capture flow cytometry provided a quantitative measurement of sickled RBC fraction decrease. This mechanism may provide a useful biomarker test in future clinical studies to monitor SG treatment effects on SCD patients. Fig. 1 SG Treatment of Sickled RBC. Hypoxic SCD RBC treated with SG, oxygenated SG or PBSA for 2 hrs prior to fixation and image capture (40X mag). Fig. 1. SG Treatment of Sickled RBC. Hypoxic SCD RBC treated with SG, oxygenated SG or PBSA for 2 hrs prior to fixation and image capture (40X mag). Disclosures Jubin: Prolong Pharmaceuticals: Employment. Buontempo:Prolong Pharmaceuticals: Employment. Yglesias:Prolong Pharmaceuticals: Employment. Abuchowski:Prolong Pharmaceuticals: Employment. Chen:Prolong Pharmaceuticals: Employment. Kazo:Prolong Pharmaceuticals: Employment. Kazo:Prolong Pharmaceuticals: Employment.
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